We have hypothesized that insulin dependent diabetes mellitus (IDDM) is genetically and environmentally heterogeneous. Each form of IDDM is likely to result from the action of a major genetic or environmental factor, interacting with the background genotype. These major factors are necessary, but not sufficient without the genetic background, to determine the disease. We further postulate that certain forms of IDDM are genetically related to insulin independent diabetes. We intend to test these hypotheses by ascertaining 1,000 diabetic Caucasian families for segregation analysis. Histocompatibility (HLA) typing, for A,B,C,Dw,DRw, and in some cases PLT with T cell clones, will be performed in 250 of these families, in 20 U.S. Indian IDDM families, 50 U.S. Black, and 50 Japanese IDDM patients. In some cases, glyoxalase, properdin, and C4 will also be studied. We also propose a prospective study of families with normal parents and two or more HLA identical IDDM children to determine whether the nondiabetic sibs, HLA identical to their diabetic siblings, are at a higher risk for IDDM, and to study the natural history of the prediabetic state with islet cell antibodies, glucose tolerance tests, capillary basement membrane, and immunohistochemistry measurements. The HLA antigens will also be studied in 500 IDDM patients with terminal diabetic kidney disease, to search for a genetic contribution to diabetic microangiopathy.